Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations

Abstract

BACKGROUND In the current study, the authors present a comprehensive genomic profile (CGP)‐based study of advanced urothelial carcinoma (UC) designed to detect clinically relevant genomic alterations (CRGAs). METHODS DNA was extracted from 40 µm of formalin‐fixed, paraffin‐embedded sections from 295 consecutive cases of recurrent/metastatic UC. CGP was performed on hybridization‐captured, adaptor ligation‐based libraries to a mean coverage depth of 688X for all coding exons of 236 cancer‐related genes plus 47 introns from 19 genes frequently rearranged in cancer, using process‐matched normal control samples as a reference. CRGAs were defined as GAs linked to drugs on the market or currently under evaluation in mechanism‐driven clinical trials. RESULTS All 295 patients assessed were classified with high‐grade (International Society of Urological Pathology classification) and advanced stage (stage III/IV American Joint Committee on Cancer) disease, and 294 of 295 patients (99.7%) had at least 1 GA on CGP with a mean of 6.4 GAs per UC (61% substitutions/insertions/deletions, 37% copy number alterations, and 2% fusions). Furthermore, 275 patients (93%) had at least 1 CRGA involving 75 individual genes with a mean of 2.6 CRGAs per UC. The most common CRGAs involved cyclin‐dependent kinase inhibitor 2A (CDKN2A) (34%), fibroblast growth factor receptor 3 (FGFR3) (21%), phosphatidylinositol 3‐kinase catalytic subunit alpha (PIK3CA) (20%), and ERBB2 (17%). FGFR3 GAs were diverse types and included 10% fusions. ERBB2 GAs were equally divided between amplifications and substitutions. ERBB2 substitutions were predominantly within the extracellular domain and were highly enriched in patients with micropapillary UC (38% of 32 cases vs 5% of 263 nonmicropapillary UC cases; P<.0001). CONCLUSIONS Using a CGP assay capable of detecting all classes of GA simultaneously, an extraordinarily high frequency of CRGA was identified in a large series of patients with advanced UC. Cancer 2016;122:702–711. © 2015 American Cancer Society.

Clinical genomic profiling to identify actionable alterations for investigational therapies in patients with diverse sarcomas

“…Previous studies have assessed genomic biomarker actionability [40, 41]. These studies included larger numbers of patients and reported high frequencies of clinically actionable genomic markers.…”

Comprehensive somatic genome alterations of urachal carcinoma

“…Interestingly, amplifications of three genes in the FGFR family were mutually exclusive in six samples, suggesting that alterations of these genes might be involved in the oncogenic process. When the genomic profiles of 295 patients with bladder cancer were examined,34 somatic mutations in FGFR3 (21% of patients) and amplifications of FGFR1 (4.7%) were common in bladder cancer. Compared with the relatively infrequent FGFR2 mutations and amplifications (3%, ≤3 cases for each alteration type) in the TCGA bladder dataset (figure 3C), the high and focal amplifications of FGFR2 observed here might be distinguishing features in urachal cancer.…”

Coexistence of YWHAZ amplification predicts better prognosis in muscle-invasive bladder cancer with CDKN2A or TP53 loss

“…CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, codes for two proteins, including p16 an p14arf, both act as tumor suppressors by regulating the cell cycle. The genetic alteration of CDKN2A is most common clinically relevant in the advanced bladder cancer [10]. Both TP53 and CDKN2A alteration contributed to the unfavorable clinical and survival outcomes [11].…”